Siglecs (sialic acid-binding immunoglobulin-like lectins) are single-pass transmembrane cell surface proteins found predominantly on leukocytes and are characterized by their specificity for sialic acids attached to cell-surface glycoconjugates. The Siglec family contains at least 15 members that are found in mammals (Pillai et al., Annu Rev Immunol., 30:357-392, 2012). These members include sialoadhesion (Siglec-1), CD22 (Siglec-2), CD33 (Siglec-3), myelin associated glycoprotein (Siglec-4), Siglec-5, OBBP1 (Siglec-6), AIRM1 (Siglec-7), SAF-2 (Siglec-8), and CD329 (Siglec-9). Siglec-8, a member that is expressed in humans but not in mouse, was first discovered as part of efforts to identify novel human eosinophil proteins. In addition to expression by eosinophils, it is also expressed by mast cells and basophils. Siglec-8 recognizes a sulfated glycan, i.e., 6′-sulfo-sialyl Lewis X or 6′-sulfo-sialyl-N-acetyl-S-lactosamine, and contains an intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM) domain shown to inhibit mast cell function.
Along with mast cells, eosinophils can promote an inflammatory response that plays a beneficial functional role such as controlling an infection at a specific tissue site. During an inflammatory response, apoptosis of eosinophils can be inhibited through the activity of survival-promoting cytokines such as IL-5 and GM-CSF. However, an increase of activated eosinophils that are not rapidly removed by apoptosis can result in the release of eosinophil granule proteins at already inflamed sites which can damage tissue and cause inflammation to be further exacerbated. Examples of diseases that arise due to biological activity of mast cells and eosinophils include chronic rhinosinusitis with nasal polyposis (CRSwNP) and aspirin-exacerbated respiratory disease (AERD), also known as Samter's Triad or aspirin-sensitive asthma. CRSwNP is a serious disease which significantly impacts quality of life, and in many cases, is poorly managed with inhaled corticosteroids. Mast-cell infiltration in the nasal polyps has been shown to be prominent in both atopic and non-atopic individuals (Ruhno et al., Allergy, 45:370-374, 1990). The nasal polyps in CRSwNP also contain large numbers of eosinophils and there is a correlation between peripheral eosinophilia with polyp eosinophil infiltration (Hu et al., Laryngoscope, 122(3):498-503, 2012) as well as disease severity (Bryson et al., Clin Otolaryngol Allied Sci., 28(1): 55-8, 2003). AERD is also a serious disease as it is strongly associated with near-fatal asthma (Szczeklik et al., Hypersensitivity to Aspirin and Nonsteroidal Anti-Inflammatory Drugs. In: Middleton's Allergy, 7th edition., Mosby Elsevier, Philadelphia, Pa., 1227-1243, 2009) and has a protracted course even after avoidance of aspirin and other non-steroidal anti-inflammatory agents (NSAIDs) (Kowalski M. L., http://www.worldallergy.org/professional/allergic_diseases_center/aspirin/, originally posted May 2006). In addition to aspirin-sensitive asthma, AERD patients have chronic rhinosinusitis with nasal polyposis. Thus the disease is also considered a sub-set of CRSwNP with 30-40% of CRS patients estimated to be hypersensitive to aspirin (Szczeklik et al., Pharmacological Report, 62:526-529, 2010). AERD is associated with eosinophilic asthma and is characterized by the growth of nasal polyps containing large numbers of both eosinophils and mast cells as well as intense infiltration of eosinophils and mast cells into the entire respiratory mucosa (Stevenson et al., Clin Rev. Allergy Immunol., 24: 169, 2003), often leading to aggressive airway remodeling (Steinke et al. J. Allergy., 2012:1-9, 2012). Up to 50% of AERD patients require systemic corticosteroids to control their asthma. However, the disease is poorly managed with inhaled or oral steroids and patients typically require repeated surgery to remove recurring nasal polyps (Jenkins et al., BMJ. 328:434, 2004). Therefore, there appears to be a need for alternative therapies that can control the activity of immune cells involved in pathogenesis of these diseases, such as the activity of eosinophils and mast cells, due to poor disease management by currently available therapeutic treatments.
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